Van 5 - inhibitors

Introduction to Enzyme Inhibitors

  • Enzyme inhibitors are molecules that interfere with enzyme catalysis.
  • Can be natural products or synthetic compounds, with many drugs acting as inhibitors.

Types of Enzyme Inhibitors

  • Irreversible Inhibitors
    • Dissociate very slowly (if at all) from the enzyme.
    • Often form covalent bonds with the enzyme.
    • Example: Suicide Inhibition
  • Reversible Inhibitors
    • Rapidly dissociate from the enzyme-inhibitor complex.
    • Subdivided into:
    • Competitive Inhibition
    • Uncompetitive Inhibition
    • Noncompetitive Inhibition
    • Mixed Inhibition

Key Parameters for Enzyme Kinetics

  • Vmax: Maximum velocity at high substrate concentrations.
  • Km: Michaelis-Menten constant; substrate concentration for half-maximal velocity.
  • Vmax/Km: Represents the rate constant proportional to the initial phase.

Characteristics of Enzyme Inhibition

  • Inhibitors change the characteristics of the enzyme in terms of:
    • Vmax
    • Km (and apparent values with inhibitors: Vmax,app, Km,app)

Competitive Inhibitors

  • Compete with substrate for the active site.
    • Resemble substrate structure.
  • Effects:
    • Increase Km (decreases affinity for substrate).
    • Vmax remains unchanged.
    • Can be overcome by increasing substrate concentration.
  • Examples:
    • Methotrexate: Inhibits dihydrofolate reductase in cancer treatment.
    • Allopurinol: Inhibits xanthine oxidase for gout treatment.
    • Statins: Inhibit HMG-CoA reductase to lower cholesterol.
    • Imatinib: Inhibits Bcr-Abl tyrosine kinase in cancer.

Uncompetitive Inhibitors

  • Bind only to the enzyme-substrate complex.
  • Effects:
    • Decrease both Km and Vmax.
    • Cannot be overcome by increasing substrate concentration.
  • Example: Lithium as an uncompetitive inhibitor of inositol monophosphatase.

Noncompetitive Inhibitors

  • Bind to both enzyme and enzyme-substrate complex with the same affinity.
  • Effects:
    • Decrease Vmax (no change in Km).
    • Cannot be overcome by substrate concentration increase.
  • Examples: Nevirapine and etravirine used for HIV.

Mixed Inhibitors

  • Bind to both enzyme and complex, but with different affinities.
  • Effects:
    • Vmax decreases; Km can increase or decrease.

Suicide Inhibitors

  • Irreversible inhibitors that become reactive upon binding, forming covalent bonds.
  • Examples:
    • Aspirin: Inhibits COX enzymes involved in prostaglandin synthesis.
    • Penicillin: Inhibits D-alanyl-D-alanine transpeptidase in bacteria.
    • Eflornithine: Inhibits ornithine decarboxylase in trypanosomes.

Quantitative Analysis of Reversible Inhibitors

  • Inhibition effects can be expressed quantitatively with parameters:
    • Ki: Equilibrium constant for free enzyme and inhibitor.
    • Ki': Equilibrium constant for enzyme-substrate and inhibitor complex.
  • Competitive, uncompetitive, non-competitive, mixed inhibition have distinct effects on Vmax and Km.